In 1980, a Brazilian-Israeli team published the first clinical trial of CBD for epilepsy: 10% of CBD patients still seizing versus 90% of placebo. The finding was ignored for four decades until desperate parents and modern trials vindicated it.
Anyone interested in the hidden history of cannabis medicine, the intersection of science and drug policy, or the origins of CBD for epilepsy.
10% still seizing (CBD) vs 90% (placebo) — 1980, ignored for 40 years
The Backstory
In 2017, when the New England Journal of Medicine published Devinsky's landmark trial showing CBD reduced seizures in Dravet syndrome, it was hailed as a breakthrough — the first rigorous evidence that cannabidiol could treat epilepsy.
It wasn't. The first rigorous evidence had been published thirty-seven years earlier, in a Brazilian pharmacology journal, by a team that included both the pioneer of Brazilian psychopharmacology and the man who had isolated THC. The scientific community ignored it for four decades.
This is the story of how the most important finding in cannabis medicine was discovered, forgotten, rediscovered, and vindicated.
The Forgotten Trial
The paper had nine authors. The senior investigators were Elisaldo Carlini — a Brazilian pharmacologist who had spent three years at Yale before founding the Department of Psychopharmacology at the São Paulo School of Medicine (UNIFESP) — and Raphael Mechoulam at the Hebrew University of Jerusalem, who had isolated THC sixteen years earlier.
Their collaboration had begun in the 1970s, when Carlini noticed something odd about Brazilian cannabis samples. The THC content alone didn't explain all the biological effects he was observing. Some extracts were sedating where pure THC was stimulating. Some were anticonvulsant where THC was not. Other cannabinoids — particularly cannabidiol — were clearly doing something.
In 1973, Carlini's group published preclinical evidence that CBD protected mice against seizure-inducing agents and blocked audiogenic seizures in rats. It also reduced seizure susceptibility in hippocampal tissue. The animal data was clear: CBD was anticonvulsant.
The logical next step was a human trial. It happened in São Paulo. And it worked.
The Study
How They Did It
The First CBD Epilepsy Trial in Humans (1980)
Phase 1: Safety in healthy volunteers
16 healthy adults were randomized in a double-blind design: 8 received CBD at 3 mg/kg/day for 30 days, 8 received placebo (glucose capsules).
Monitored via neurological exams, blood tests, EEG, and ECG
Phase 1 result
CBD was well tolerated. No signs of toxicity or serious side effects detected. All volunteers completed the 30-day course. Safety established.
This was the first evidence that chronic CBD use is safe in humans
Phase 2: Efficacy in epilepsy patients
15 adults with treatment-resistant temporal lobe epilepsy received either CBD (200-300 mg daily) or placebo for up to 4.5 months, added to their existing anti-epileptic drugs. Double-blind design.
Drug-resistant = failed conventional anti-epileptic medications
Phase 2 result
4 of 8 CBD patients became almost completely seizure-free. 3 showed partial improvement. 1 showed no improvement. In the placebo group: 1 improved, 6 unchanged, and 1 worsened.
Only 10% of CBD patients still had generalized seizures at study end, versus 90% of placebo patients
Cunha et al. (1980), Pharmacology 21:175-185
10% vs. 90%
of patients still experiencing generalized epileptic seizures at the end of treatment — CBD group versus placebo group. In a small trial of 15 drug-resistant epilepsy patients, CBD virtually eliminated generalized seizures in most patients who received it. The placebo group showed almost no improvement.
For comparison, the 2017 NEJM Dravet trial showed 38.9% seizure reduction with CBD vs 13.3% with placebo. The 1980 trial's results were, if anything, more dramatic — though the sample size was far smaller.
Cunha et al. (1980), Pharmacology 21:175-185
The results were remarkable. In a double-blind, placebo-controlled trial — the gold standard even in 1980 — CBD had virtually eliminated generalized seizures in most patients. The safety profile was clean. The methodology was sound.
And then nothing happened.
Forty Years of Silence
The result was a four-decade gap. From 1980 to the 2010s, no major clinical trial of CBD for epilepsy was conducted. The Cunha study sat in the literature, occasionally cited in reviews, never replicated, never followed up.
Rediscovery
The rediscovery didn't come from scientists. It came from parents.
In 2013, the Figi family's story broke on CNN — Charlotte, a girl with Dravet syndrome, dramatically improving on CBD-rich cannabis oil. A 2013 Stanford retrospective study of 19 children with refractory epilepsy found over 80% seizure reduction in 52% of CBD users. The anecdotes accumulated. The desperation was undeniable. And researchers finally went back to the literature and found that a Brazilian team had already demonstrated this — in a double-blind trial — thirty-three years earlier.
Devinsky's expanded access program launched in 2014. The NEJM Dravet trial was published in 2017. The LGS trial followed in 2018. Epidiolex was approved in June 2018.
Mechoulam lived to see the vindication. Carlini, who died in September 2020 at age 90, saw his forgotten work become the historical foundation of an FDA-approved drug.
Research Timeline
CBD for Epilepsy: Discovered, Forgotten, Vindicated
Carlini's group shows CBD is anticonvulsant in animals
Mice protected from seizure-inducing agents. Hippocampal tissue showed reduced seizure susceptibility. The preclinical foundation.
Partial clinical results published
Preliminary data from the São Paulo trial — the first hint of human efficacy
Full trial published
15 epilepsy patients, double-blind, placebo-controlled: 10% of CBD patients still seizing vs 90% of placebo. Ignored for 40 years.
Four decades of silence
No major clinical trial of CBD for epilepsy conducted. War on Drugs, regulatory barriers, and the assumption that CBD was 'inactive' kill follow-up research.
Charlotte Figi story airs on CNN
A child with Dravet syndrome improves dramatically on CBD oil. Parents begin moving to Colorado. The scientific establishment is forced to respond.
Modern RCTs confirm the 1980 finding
Devinsky (Dravet) and Thiele (LGS) publish gold-standard trials in NEJM and Lancet. The results match what Cunha and Carlini showed four decades earlier.
FDA approves Epidiolex
The first cannabis-derived prescription drug — vindicating a finding that was ignored since 1980
Cunha et al. (1980); Devinsky et al. (2017); Thiele et al. (2018)
What This Study Teaches
Myth vs. Reality
CBD for epilepsy was discovered by parents in Colorado in 2013.
Parents in Colorado brought CBD for epilepsy to public attention. Brazilian scientists discovered it in a clinical trial in 1980 — and in animal studies in 1973. The Cunha trial was double-blind, placebo-controlled, and showed dramatic results. It was ignored for forty years due to the War on Drugs, regulatory barriers, the small sample size, and the prevailing assumption that CBD was pharmacologically inert. The modern Epidiolex trials confirmed what Carlini and Mechoulam had demonstrated decades earlier.
The Evidence
Cunha et al. (1980): 10% of CBD patients still seizing vs 90% placebo over 4.5 months. Carlini et al. (1973): CBD anticonvulsant in mice and rat hippocampal tissue. Devinsky et al. (2017): 38.9% seizure reduction in Dravet (NEJM). The timeline shows discovery preceded rediscovery by 37 years.
Cunha et al. (1980), Pharmacology 21:175-185; Carlini et al. (1973)
This paper is a cautionary tale about how science actually works — and how it sometimes doesn't. A positive clinical trial, published by credible investigators with NIH funding, in a peer-reviewed journal, can be buried for decades if the political climate, regulatory framework, and prevailing assumptions are hostile to its implications.
The families who moved to Colorado in 2013 didn't know they were rediscovering a forty-year-old finding. The scientists who ran the modern Epidiolex trials knew — and acknowledged the Brazilian legacy. The vindication was complete, but it came too late for the thousands of epilepsy patients who lived through those lost decades without access to a treatment that had already been shown to work.
“It seemed a very promising approach, but unfortunately, nothing has been done ever since.”
— Raphael Mechoulam
Hebrew University of Jerusalem
Reflecting on the decades of silence after the 1980 trial he co-authored with Carlini
Related Research
The CBD Epilepsy Arc: 1980-2018
This 1980 trial is the beginning of a story that took 38 years to reach its conclusion.
Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial
Devinsky et al. (2016)
The modern rediscovery — 214 patients, 36.5% seizure reduction, plus the NEJM Dravet RCT that confirmed what Cunha showed in 1980
CBD for Lennox-Gastaut syndrome (GWPCARE4)
Thiele et al. (2018)
The second confirmation — CBD works for LGS too. Together with Dravet, completed the Epidiolex approval package.
Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish
Gaoni & Mechoulam (1964)
Mechoulam co-authored both the THC isolation and the first CBD epilepsy trial — bookending cannabis pharmacology
A tale of two cannabinoids: THC and CBD therapeutic rationale
Russo & Guy (2006)
The paper that argued CBD had independent therapeutic value — 26 years after this trial already showed it
Was this really the first CBD trial for epilepsy?
Yes. Cunha et al. (1980) is the first published double-blind, placebo-controlled clinical trial of CBD for epilepsy in humans. Carlini's group had published preliminary results in 1978 and preclinical (animal) data as early as 1973. No earlier human clinical trial of CBD for seizures exists in the published literature.
Why was it ignored for 40 years?
Multiple factors: the War on Drugs made cannabis research politically radioactive; CBD was classified as Schedule I with "no accepted medical use"; the sample size (15 patients) was small by modern standards; the publication venue was not high-profile; no pharmaceutical company had incentive to fund follow-up trials for an unpatentable natural compound; and the prevailing scientific assumption was that CBD was pharmacologically inert. Together, these factors created a perfect storm of neglect.
How do the 1980 results compare to modern trials?
Remarkably well. Cunha found that only 10% of CBD patients still had generalized seizures versus 90% of placebo patients — a dramatic difference, though in only 15 patients. The modern Epidiolex trials (120-171 patients each) found 38.9-43.9% seizure reduction versus 13.3-21.8% with placebo. The modern trials are more rigorous and much larger, but the direction and magnitude of the finding were already clear in 1980.
What the researchers found
The first-ever clinical trial of CBD for epilepsy. In 15 adults with drug-resistant temporal lobe epilepsy, CBD (200-300 mg/day) virtually eliminated generalized seizures: only 10% of CBD patients still seizing at study end versus 90% of placebo patients. CBD was well tolerated with no serious side effects. The finding was ignored for 40 years.
Why it matters
This is the earliest clinical evidence that CBD reduces seizures in humans. Published in 1980, it predated the modern Epidiolex trials by 37 years. The results were dramatic but ignored due to the War on Drugs, regulatory barriers, CBD's Schedule I status, and the prevailing assumption that CBD was pharmacologically inert. The 2017-2018 Epidiolex trials vindicated what this study already showed.
The numbers in context
Phase 1: 16 healthy volunteers (8 CBD at 3 mg/kg/day, 8 placebo) for 30 days. Phase 2: 15 epilepsy patients (8 CBD at 200-300 mg/day, 7 placebo) for up to 4.5 months. CBD group: 4/8 almost seizure-free, 3/8 partial improvement. Placebo: 1/7 improved, 6/7 unchanged or worsened. 10% CBD still seizing vs 90% placebo.
How the study worked
Two-phase double-blind, placebo-controlled trial. Phase 1: safety in healthy volunteers (CBD 3 mg/kg/day for 30 days). Phase 2: efficacy in drug-resistant epilepsy (CBD 200-300 mg/day for up to 4.5 months as add-on therapy). Monitored with neurological exams, blood tests, EEG, ECG.
Who was studied
Phase 1: 16 healthy adult volunteers. Phase 2: 15 adults with drug-resistant temporal lobe epilepsy.
What this study cannot tell us
Very small sample size (15 epilepsy patients). Single-center. 1980 methodology standards differ from modern trial requirements. No long-term follow-up published. The dramatic results were never replicated until the 2010s. Published in a low-impact journal.
How to read the evidence
Double-blind, placebo-controlled design (gold standard), but very small sample size (n=15 for efficacy) and published in a low-impact journal. The results were dramatic but underpowered by modern standards. The finding was not replicated for 37 years, when the Epidiolex trials confirmed it at scale.
When this study was published
Published in 1980. The oldest study in the CBD epilepsy cluster and one of the oldest in the entire pillar study collection. Its results were vindicated 37 years later by the Devinsky (2017) and Thiele (2018) RCTs.
The bigger picture
This is a cautionary tale about how science interacts with politics. A positive, double-blind clinical trial showing a cannabis compound reduces seizures was buried for four decades because the political and regulatory environment was hostile to cannabis research. Thousands of epilepsy patients lived through those lost decades without access to a treatment that had already been shown to work.
Questions still open
- How many other cannabis research findings from the 1970s-1980s have been similarly forgotten? Would earlier follow-up have accelerated the timeline to Epidiolex by decades? How much human suffering resulted from the 40-year delay?
Common questions
Read the original research
Chronic administration of cannabidiol to healthy volunteers and epileptic patients
Pharmacology
Pharmacology — a peer-reviewed journal publishing research on drug action and therapeutics, published by Karger since 1968.
Citation
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. https://doi.org/10.1159/000137430